rs151344481
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000397.4(CYBB):c.170C>A(p.Ala57Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
CYBB
NM_000397.4 missense
NM_000397.4 missense
Scores
11
5
1
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
CYBB (HGNC:2578): (cytochrome b-245 beta chain) Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a domain Ferric oxidoreductase (size 232) in uniprot entity CY24B_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000397.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant X-37783518-C-A is Pathogenic according to our data. Variant chrX-37783518-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 68391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37783518-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYBB | NM_000397.4 | c.170C>A | p.Ala57Glu | missense_variant | 3/13 | ENST00000378588.5 | NP_000388.2 | |
CYBB | XM_047441855.1 | c.-261C>A | 5_prime_UTR_variant | 1/12 | XP_047297811.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.170C>A | p.Ala57Glu | missense_variant | 3/13 | 1 | NM_000397.4 | ENSP00000367851.4 | ||
ENSG00000250349 | ENST00000465127.1 | c.171+357518C>A | intron_variant | 5 | ENSP00000417050.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2015 | The A57E missense variant in the CYBB gene has been reported previously in association with X-linkedchronic granulomatous disease (Ariga et al., 1993). It was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. A57E is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species and in-silico analysispredicts this variant is probably damaging to the protein structure/function. In addition, missense variants innearby residues (A53D, R54G/M/S, A55D, P56L, C59R/F/Y/W, N63K, C64R, M65R, L66P) have beenreported in the Human Gene Mutation Database in association with chronic granulomatous disease (Stenson etal., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret A57E as a pathogenic variant. - |
Granulomatous disease, chronic, X-linked Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CYBB protein function (PMID: 21659519). In addition, advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYBB protein function. This variant has been observed in individuals affected with X-linked chronic granulomatous disease (PMID: 8101486, 10914676, 30470980). ClinVar contains an entry for this variant (Variation ID: 68391). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 57 of the CYBB protein (p.Ala57Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of methylation at R54 (P = 0.0998);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at